scholarly journals Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

2020 ◽  
Vol 6 (49) ◽  
pp. eabc8696
Author(s):  
Noboru J. Sakabe ◽  
Ivy Aneas ◽  
Nicholas Knoblauch ◽  
Debora R. Sobreira ◽  
Nicole Clark ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Stromal Cells ◽  
Target Genes ◽  
Association Studies ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Functional Annotations ◽  
Gestational Duration

While a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWASs), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of functional genomic annotations in human cell types relevant to pregnancy and PTB. We generated transcriptome (RNA-seq), epigenome (ChIP-seq of H3K27ac, H3K4me1, and H3K4me3 histone modifications), open chromatin (ATAC-seq), and chromatin interaction (promoter capture Hi-C) annotations of cultured primary decidua-derived mesenchymal stromal/stem cells and in vitro differentiated decidual stromal cells and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. Using these resources, we uncovered additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

scholarly journals Transcriptome and regulatory maps of decidua-derived stromal cells inform gene discovery in preterm birth

2020 ◽  
Author(s):  
Noboru Sakabe ◽  
Ivy Aneas ◽  
Nicholas Knoblauch ◽  
Debora R. Sobreira ◽  
Nicole Clark ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Stromal Cells ◽  
Target Genes ◽  
Association Studies ◽  
Cell Types ◽  
Genome Wide Association Studies ◽  
Functional Annotations ◽  
Significant Enrichment ◽  
Gestational Duration

AbstractWhile a genetic component of preterm birth (PTB) has long been recognized and recently mapped by genome-wide association studies (GWAS), the molecular determinants underlying PTB remain elusive. This stems in part from an incomplete availability of comprehensive functional genomic annotations in human cell types relevant to pregnancy and PTB. Here, we generated extensive transcriptional and chromatin annotations of cultured primary decidua-derived mesenchymal stromal/stem cells (MSCs) and in vitro differentiated decidual stromal cells (DSCs) and developed a computational framework to integrate these functional annotations with results from a GWAS of gestational duration in 56,384 women. This resulted in a significant enrichment of heritability estimates in functional noncoding regions in stromal cells, as well as in the discovery of additional loci associated with gestational duration and target genes of associated loci. Our strategy illustrates how systematic functional annotations in pregnancy-relevant cell types aid in the experimental follow-up of GWAS for PTB and, likely, other pregnancy-related conditions.

scholarly journals Analysis of putative cis-regulatory elements regulating blood pressure variation

2020 ◽  
Vol 29 (11) ◽  
pp. 1922-1932
Author(s):  
Priyanka Nandakumar ◽  
Dongwon Lee ◽  
Thomas J Hoffmann ◽  
Georg B Ehret ◽  
Dan Arking ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Association Studies ◽  
Specific Effect ◽  
Cell Types ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Functional Scores ◽  
Cell Type Specific

Abstract Hundreds of loci have been associated with blood pressure (BP) traits from many genome-wide association studies. We identified an enrichment of these loci in aorta and tibial artery expression quantitative trait loci in our previous work in ~100 000 Genetic Epidemiology Research on Aging study participants. In the present study, we sought to fine-map known loci and identify novel genes by determining putative regulatory regions for these and other tissues relevant to BP. We constructed maps of putative cis-regulatory elements (CREs) using publicly available open chromatin data for the heart, aorta and tibial arteries, and multiple kidney cell types. Variants within these regions may be evaluated quantitatively for their tissue- or cell-type-specific regulatory impact using deltaSVM functional scores, as described in our previous work. We aggregate variants within these putative CREs within 50 Kb of the start or end of ‘expressed’ genes in these tissues or cell types using public expression data and use deltaSVM scores as weights in the group-wise sequence kernel association test to identify candidates. We test for association with both BP traits and expression within these tissues or cell types of interest and identify the candidates MTHFR, C10orf32, CSK, NOV, ULK4, SDCCAG8, SCAMP5, RPP25, HDGFRP3, VPS37B and PPCDC. Additionally, we examined two known QT interval genes, SCN5A and NOS1AP, in the Atherosclerosis Risk in Communities Study, as a positive control, and observed the expected heart-specific effect. Thus, our method identifies variants and genes for further functional testing using tissue- or cell-type-specific putative regulatory information.

scholarly journals Heritability enrichment implicates microglia in Parkinson’s disease pathogenesis

2020 ◽  
Author(s):  
Maren Stolp Andersen ◽  
Sara Bandres-Ciga ◽  
Regina H. Reynolds ◽  
John Hardy ◽  
Mina Ryten ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Risk ◽  
Association Studies ◽  
Cell Types ◽  
Polygenic Risk Score ◽  
Open Chromatin ◽  
Specific Cell ◽  
Genome Wide Association Studies ◽  
Therapeutic Implications

AbstractObjectiveUnderstanding how different parts of the immune system contribute to pathogenesis in Parkinson’s disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson’s disease stratified by immune and brain cell types.MethodsWe used summary statistics from the most recent meta-analysis of genome-wide association studies in Parkinson’s disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus.ResultsWe found significant enrichment of Parkinson’s disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these two cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the anti-thrombotic agent clopidogrel, as the likely driver of a significant Parkinson’s disease association signal on chromosome 3.InterpretationOur results provide further support for the importance of immune mechanisms in PD pathogenesis, highlight microglial dysregulation as a contributing etiological factor and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson’s disease.

scholarly journals Chromatin interactome mapping at 139 independent breast cancer risk signals

2019 ◽  
Author(s):  
Jonathan Beesley ◽  
Haran Sivakumaran ◽  
Mahdi Moradi Marjaneh ◽  
Luize G. Lima ◽  
Kristine M. Hillman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Target Genes ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Breast Cancer Cell Lines ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Candidate Target

ABSTRACTGenome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals, and explore the functional mechanism underlying altered risk at the 12q24 risk region. Our results demonstrate the power of combining genetics, computational genomics and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

scholarly journals A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids

2021 ◽  
Author(s):  
Shweta Ramdas ◽  
Jonathan Judd ◽  
Sarah E Graham ◽  
Stavroula Kanoni ◽  
Yuxuan Wang ◽  
...  
Keyword(s):  
Association Studies ◽  
Density Lipoprotein ◽  
Genomic Analysis ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Functional Genomic ◽  
Selective Enrichment ◽  
Functional Genomic Analysis

AbstractA major challenge of genome-wide association studies (GWAS) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations, and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels, and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. Two prioritized genes, CREBRF and RRBP1, show convergent evidence across functional datasets supporting their roles in lipid biology.

scholarly journals Schizophrenia Risk Alleles Often Affect The Expression of Many Genes and Each Gene May Have a Different Effect On The Risk; A Mediation Analysis

2020 ◽  
Author(s):  
Xi Peng ◽  
Joel S. Bader ◽  
Dimitrios Avramopoulos
Keyword(s):  
Gene Expression ◽  
Mediation Analysis ◽  
Target Genes ◽  
Risk Allele ◽  
Association Studies ◽  
Cell Types ◽  
Developmental Time ◽  
Genome Wide Association Studies ◽  
Expression Change ◽  
Risk Alleles

ABSTRACTVariants identified by genome-wide association studies (GWAS) are often expression quantitative trait loci (eQTLs), suggesting they are proxies or are themselves regulatory. Across many datasets analyses show that variants often affect multiple genes. Lacking data on many tissue types, developmental time points and homogeneous cell types, the extent of this one-to-many relationship is underestimated. This raises questions on whether a disease eQTL target gene explains the genetic association or is a by-stander and puts into question the direction of expression effect of on the risk, since the many variant - regulated genes may have opposing effects, imperfectly balancing each other. We used two brain gene expression datasets (CommonMind and BrainSeq) for mediation analysis of schizophrenia-associated variants. We confirm that eQTL target genes often mediate risk but the direction in which expression affects risk is often different from that in which the risk allele changes expression. Of 38 mediator genes significant in both datasets 33 showed consistent mediation direction (Chi2 test P=6*10−6). One might expect that the expression would correlate with the risk allele in the same direction it correlates with disease. For 15 of these 33 (45%), however, the expression change associated with the risk allele was protective, suggesting the likely presence of other target genes with overriding effects. Our results identify specific risk mediating genes and suggest caution in interpreting the biological consequences of targeted modifications of gene expression, as not all eQTL targets may be relevant to disease while those that are, might have different than expected directions.

scholarly journals Can cancer GWAS variants modulate immune cells in the tumor microenvironment?

2018 ◽  
Author(s):  
Yi Zhang ◽  
Mohith Manjunath ◽  
Jialu Yan ◽  
Brittany A. Baur ◽  
Shilu Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cells ◽  
Cancer Susceptibility ◽  
Association Studies ◽  
Immune Surveillance ◽  
Tumor Infiltrating Lymphocytes ◽  
Cell Types ◽  
Potential Effect ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies

AbstractGenome-wide association studies (GWAS) have hitherto identified several genetic variants associated with cancer susceptibility, but the molecular functions of these risk modulators remain largely uncharacterized. Recent studies have begun to uncover the regulatory potential of non-coding GWAS SNPs by using epigenetic information in corresponding cancer cell types and matched normal tissues. However, this approach does not explore the potential effect of risk germline variants on other important cell types that constitute the microenvironment of tumor or its precursor. This paper presents evidence that the breast cancer-associated variant rs3903072 may regulate the expression of CTSW in tumor infiltrating lymphocytes. CTSW is a candidate tumor-suppressor gene, with expression highly specific to immune cells and also positively correlated with breast cancer patient survival. Integrative analyses suggest a putative causative variant in a GWAS-linked enhancer in lymphocytes that loops to the 3’ end of CTSW through three-dimensional chromatin interaction. Our work thus poses the possibility that a cancer-associated genetic variant might regulate a gene not only in the cell of cancer origin, but also in immune cells in the microenvironment, thereby modulating the immune surveillance by T lymphocytes and natural killer cells and affecting the clearing of early cancer initiating cells.

scholarly journals An Effector Index to Predict Target Genes at GWAS Loci

2021 ◽  
Author(s):  
Vincenzo Forgetta ◽  
Lai Jiang ◽  
Nicholas Vulpescu ◽  
Meganq Hogan ◽  
Siyuan Chen ◽  
...  
Keyword(s):  
Drug Development ◽  
Target Genes ◽  
Association Studies ◽  
Predictive Performance ◽  
Positive Control ◽  
Open Chromatin ◽  
Genome Wide Association Studies ◽  
Genetic Associations ◽  
Single Nucleotide Variants ◽  
Common Diseases

Abstract Drug development and biological discovery require effective strategies to map existing genetic associations to causal genes. To approach this problem, we selected 12 common diseases and quantitative traits for which highly powered genome-wide association studies (GWAS) were available. For each disease or trait, we systematically curated positive control gene sets from Mendelian forms of the disease and from targets of medicines used for disease treatment. We found that these positive control genes were highly enriched in proximity of GWAS-associated single nucleotide variants (SNVs). We then performed quantitative assessment of the contribution of commonly used genomic features, including open chromatin maps, expression quantitative trait loci (eQTL), and chromatin conformation data. Using these features, we trained and validated an Effector Index (Ei), to map target genes for these 12 common diseases and traits. Ei demonstrated high predictive performance, both with cross-validation on the training set, and an independently derived set for type 2 diabetes. Key predictive features included coding or transcript altering SNVs, distance to gene, and open chromatin-based metrics. This work outlines a simple, understandable approach to prioritize genes at GWAS loci for functional follow-up and drug development, and provides a systematic strategy for prioritization of GWAS target genes.

scholarly journals The prostate cancer risk variant rs55958994 regulates multiple gene expression through extreme long-range chromatin interaction to control tumor progression

2019 ◽  
Vol 5 (7) ◽  
pp. eaaw6710 ◽  
Author(s):  
Yuyang Qian ◽  
Lei Zhang ◽  
Mingyang Cai ◽  
Hongxia Li ◽  
Heming Xu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Long Range ◽  
Cancer Progression ◽  
Target Genes ◽  
Association Studies ◽  
Prostate Cancer Risk ◽  
Chromatin Interaction ◽  
Genome Wide Association Studies ◽  
Chromosome Conformation ◽  
Increased Risk

Genome-wide association studies identified single-nucleotide polymorphism (SNP) rs55958994 as a significant variant associated with increased susceptibility to prostate cancer. However, the mechanisms by which this SNP mediates increased risk to cancer are still unknown. In this study, we show that this variant is located in an enhancer active in prostate cancer cells. Deletion of this enhancer from prostate tumor cells resulted in decreased tumor initiation, tumor growth, and invasive migration, as well as a loss of stem-like cells. Using a combination of capture chromosome conformation capture (Capture-C) and RNA sequencing, we identified genes on the same and different chromosomes as targets regulated by the enhancer. Furthermore, we show that expression of individual candidate target genes in an enhancer-deleted cell line rescued different aspects of tumorigenesis. Our data suggest that the rs55958994-associated enhancer affects prostate cancer progression by influencing expression of multiple genes via long-range chromatin interactions.

scholarly journals EpiRegio: analysis and retrieval of regulatory elements linked to genes

2020 ◽  
Vol 48 (W1) ◽  
pp. W193-W199 ◽  
Author(s):  
Nina Baumgarten ◽  
Dennis Hecker ◽  
Sivarajan Karunanithi ◽  
Florian Schmidt ◽  
Markus List ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Association Studies ◽  
Web Server ◽  
Cell Types ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Genome Wide Association Studies ◽  
Coding Regions ◽  
Genomic Regions

Abstract A current challenge in genomics is to interpret non-coding regions and their role in transcriptional regulation of possibly distant target genes. Genome-wide association studies show that a large part of genomic variants are found in those non-coding regions, but their mechanisms of gene regulation are often unknown. An additional challenge is to reliably identify the target genes of the regulatory regions, which is an essential step in understanding their impact on gene expression. Here we present the EpiRegio web server, a resource of regulatory elements (REMs). REMs are genomic regions that exhibit variations in their chromatin accessibility profile associated with changes in expression of their target genes. EpiRegio incorporates both epigenomic and gene expression data for various human primary cell types and tissues, providing an integrated view of REMs in the genome. Our web server allows the analysis of genes and their associated REMs, including the REM’s activity and its estimated cell type-specific contribution to its target gene’s expression. Further, it is possible to explore genomic regions for their regulatory potential, investigate overlapping REMs and by that the dissection of regions of large epigenomic complexity. EpiRegio allows programmatic access through a REST API and is freely available at https://epiregio.de/.

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